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Sodium Channel Blocker Compositions and the Use

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Sodium Channel Blocker Compositions and the Use Europäisches Patentamt *EP001169060B1* (19) European Patent Office Office européen des brevets (11) EP 1 169 060 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: A61K 45/06, A61K 31/55, of the grant of the patent: A61K 31/53, A61K 31/195, 31.08.2005 Bulletin 2005/35 A61P 29/00 (21) Application number: 00923183.8 (86) International application number: PCT/US2000/009387 (22) Date of filing: 10.04.2000 (87) International publication number: WO 2000/061188 (19.10.2000 Gazette 2000/42) (54) SODIUM CHANNEL BLOCKER COMPOSITIONS AND THE USE THEREOF NATRIUM KANALBLOCKER ZUSAMMENSETZUNGEN UND DEREN VERWENDUNG COMPOSITION DE BLOCAGE DU CANAL SODIQUE ET LEUR UTILISATION (84) Designated Contracting States: (74) Representative: AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Cornish, Kristina Victoria Joy et al MC NL PT SE Kilburn & Strode, 20 Red Lion Street (30) Priority: 09.04.1999 US 128543 P London WC1R 4PJ (GB) (43) Date of publication of application: (56) References cited: 09.01.2002 Bulletin 2002/02 WO-A-98/07447 FR-A- 2 756 738 (73) Proprietor: Euro-Celtique S.A. • C.SOLARO E.A.: "A patient with multiple 2330 Luxembourg (LU) sclerosis and Down’s syndrome with a rare paroxysmal symptom at onset" EUROPEAN (72) Inventor: LAN, Nancy, C. JOURNAL OF NEUROLOGY, vol. 6, no. 4, 1999, South Pasadena, CA 91030 (US) pages 505-507, XP000938973 Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 169 060 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 169 060 B1 Description Background of the Invention 5 Field of the Invention [0001] This invention is in the field of medicinal chemistry. In particular, the invention relates to compositions com- prising blockers of sodium (Na+) channels and at least one of gabapentin or pregabalin. The invention also relates to compositions for use in the treatment of chronic pain or convulsions comprising coadministering a sodium channel 10 blocker and at least one of gabapentin or pregablin. Related Background Art [0002] Several classes of therapeutically useful drugs, including local anesthetics such as lidocaine and bupivacaine, 15 antiarrhythmics such as propafenone and amioclarone, and anticonvulsants such as lamotrigine, phenytoin and car- bamazepine, have been shown to share a common mechanism of action by blocking or modulating Na+ channel activity (Catterall, W.A., Trends Pharmacol Sci. 8:57-65 (1987)). Each of these agents is believed to act by interfering with the rapid influx of Na+ ions. Recently, other Na+ channel blockers such as BW619C89 and lifarizine have been shown to be neuroprotective in animal models of global and focal ischemia and are presently in clinical trials (Graham et al., J. 20 Pharmacol. Exp. Ther. 269:854-859 (1994); Brown et al., British J. Pharmacol. 115:1425-1432 (1995); SCRIP 1870: 8 (1993); SCRIP 1773:14 (1992)). [0003] The neuroprotective activity of Na+ channel blockers is due to their effectiveness in decreasing extracellular glutamate concentration during ischemia by inhibiting the release of this excitotoxic amino acid neurotransmitter. Stud- ies have shown that unlike glutamate receptor antagonists, Na+ channel blockers prevent hypoxic damage to mam- 25 malian white matter (Stys et al., J. Neurosci. 12:430-439 (1992)). Thus, they may offer advantages for treating certain types of strokes or neuronal trauma where damage to white matter tracts is prominent. [0004] Another example of clinical use of a Na+ channel blocker is riluzole. This drug has been shown to prolong survival in a subset of patients with ALS (Bensimm et al., New Engl. J. Med. 330:585-591 (1994)) and has subsequently been approved by the FDA for the treatment of ALS. In addition to the above-mentioned clinical uses, carbamazepine, 30 lidocaine and phenytoin are occasionally used to treat neuropathic pain, such as from trigeminal neurologia, diabetic neuropathy and other forms of nerve damage (Taylor and Meldrum, Trends Pharmacol. Sci. 16:309-316 (1995)), and carbamazepine and lamotrigine have been used for the treatment of manic depression (Denicott et al., J. Clin. Psy- chiatry 55: 70-76 (1994)). [0005] It has been established that there are at least five to six sites on the voltage-sensitive Na+ channels which 35 bind neurotoxins specifically (Catterall, W.A., Science 242:50-61 (1988)). Studies have further revealed that therapeutic antiarrhythmics, anticonvulsants and local anesthetics whose actions are mediated by Na+ channels, exert their action by interacting with the intracellular side of the Na+ channel and allosterically inhibiting interaction with neurotoxin re- ceptor site 2 (Catterall, W.A., Ann. Rev. Pharmacol. Toxicol. 10:15-43 (1980)). [0006] Chronic pain or neuropathic pain is a heterogenous disease state with an unclear etiology. In chronic pain, 40 the pain can be mediated by multiple mechanisms. This type of pain generally arises from injury to the peripheral or central nervous tissue. The syndromes include pain associated with spinal cord injury, multiple sclerosis, post-herpetic neuralgia, trigeminal neuralgia, phantom pain, causalgia and reflex sympathetic dystrophy and lower back pain. The chronic pain is different from acute pain in that patients suffer the abnormal pain sensations that can be described as spontaneous pain, continuous superficial burning and/or a deep aching pain. The pain can be evoked by heat-, cold- 45 and mechano-hyperalgesia or by heat-, cold- and mechano-allodynia (International association for the study of pain: The classification of chronic pain (1995); Bennett G.J. Molecular Neurobiology of Pain, Progress in Pain Research and Management Vol. 9, pp. 109-113, edited by D. Borsook, 1997). In most cases, chronic neuropathic pain responds poorly to treatment with opiates or nonsteroidal anti-inflammatory analgesia. [0007] Carbamazepine (Tegretol™), a sodium channel blocker anticonvulsant, has been shown to be effective in 50 trigeminal neuralgia. However, one third of patients cannot tolerate the drug in the dose required to alleviate the pain (Victor et al., Harrison's Principles of Internal Medicine. 11th ed. New York: McGraw-Hill 1987; 2035-40). In addition, carbamazepine may cause aplastic anemia, agranulocytosis, and hypersensitivity reaction (Canavero et al., Pain 60: 229-31 (1995)). These serious side effects are dose related. Carbamazepine is the only drug approved by the FDA for this indication. 55 [0008] There are no other drugs thus far that have been approved for chronic pain. Lamotrigine (Lamictal) is a sodium channel blocker that has been approved by the FDA for treating convulsions. This drug has also been shown to be effective for treating chronic pain (Lundardi et al., Neurology 48: 1714 (1997)). However, the doses required for the treatment of chronic pain are relatively high and result in side effects. The major side effect of this drug is severe, 2 EP 1 169 060 B1 potentially life-threatening rashes (Dichter and Brodie, New Engl. J. Med. 334: 1583 (1996)). [0009] Gabapentin (Neurontin™), an anticonvulsant with unknown mechanism of action has been shown recently to be efficacious for treating chronic pain (Rowbotham et al., JAMA 280: 1837-1842 (1998) and Backonja et al., JAMA 280: 1831-1836 (1998)). However, higher doses are necessary to treat chronic pain. Side effects such as exacerbated 5 absence seizures and nausea are associated with these high doses in addition to being fetotoxic. In addition, in clinical trials, gabapentin showed limited efficacy (i.e., less than 50% of patient population showed effectiveness, whereas 15-20% of patients treated with placebo showed effectiveness). [0010] Pregabalin is a potent follow-up compound to gabapentin. The compound has similar activity to gabapentin and is currently under clinical trials for neuropathic pain (SCRIP 2330:8 (1998)). 10 [0011] Thus, a need exists for treatments of chronic pain and convulsions that avoid the side effects exhibited by lamotrigine, carbamazepine and gabapentin. The present invention provides compositions and methods which reduces such side effects and improves the response rate of patients. Summary of the Invention 15 [0012] The present invention relates to pharmaceutical compositions, comprising a first agent which is a sodium channel blocker, and a second agent selected from the group consisting of gabapentin, pregabalin, salts thereof and combinations thereof; wherein the total amount of said first agent and said second agent is effective to treat, prevent or ameliorate chronic pain or convulsions. Preferably, said first agent and said second agent are present in synergistic 20 amounts, that is the sodium channel blocker and at least one of gabapentin or pregabalin or their salts are present in amounts lower than those used to treat or prevent chronic pain or convulsions when used alone. The invention further relates to such compositions that further comprise a pharmaceutically acceptable, carrier, and optionally include phar- maceutically acceptable excipients. [0013] The invention also relates to a first agent which is a sodium channel blocker, and a second agent selected 25 from the group consisting of gabapentin, pregabalin, salts thereof and combinations thereof for use in treating, pre- venting or ameliorating chronic pain or convulsions; wherein the total amount of said first agent and said second agent is effective to treat, prevent or ameliorate chronic pain or convulsions. Preferably, said sodium channel blocker and at least one of gabapentin and pregabalin are administered in synergistic amounts. Preferably, the two agents are ad- ministered substantially simultaneously as defined herein. The sodium channel blocker and at least one and pregabalin 30 may be administered separately or as part of a single pharmaceutical composition.
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